DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 15 July 2026 have been entered. Claims 1 and 138-156 were previously pending in the application. Claims 139 and 142 have been cancelled, and no new claims have been added by Applicant.
Claims 1, 138, 140-141, and 143-156 are currently pending in the application. Claims 1, 145, 147, 151, and 153 are independent claims.
The election of Group I, drawn to a circular engineered guide RNA, a nucleic acid encoding a linear precursor of the circular engineered guide RNA, and a vector comprising the nucleic acid, remains in effect in the instant application.
The following election of species remains in effect in the instant application:
IDUA target RNA Sequences: SEQ ID NO: 1418
Claims 151-156 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 138, 140-141, and 143-150 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2022/011187, filed 04 January 2022, which claims priority to U.S. Provisional Application Nos. 63/133,727, filed 04 January 2021, and 63/280,605, filed 17 November 2021.
Thus, the earliest possible priority for the instant application is 04 January 2021.
Drawings
The objection to the drawings of the disclosure for reciting "(cont’d)" in Figure 9 is withdrawn.
Specification
The objection to the specification of the disclosure for reciting trade names and/or marks without the accompanying symbol and/or generic terminology is withdrawn in view of the amendment to the specification. The amendment to the specification of the disclosure filed 15 July 2026 has been entered.
Claim Objections
The objection to amended and previously presented claims 1, 138, and 140-141 for reciting “IDUA” without first writing out the full term is withdrawn in view of the amendment to claim 1 writing out “alpha-L-iduronidase (IDUA)”.
**The following new objection is necessitated by Applicant’s amendments to the claims.
Amended claim 1 is newly objected to because of the following informalities: claim 1 recites “a a 100-200” on lines 1-2, which appears to be a duplication error of the word “a”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and cancelled claims 1 and 138-150 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn in view of Applicant’s amendments to the claims.
**The following new rejection is necessitated by Applicant’s amendments to the claims.
Amended and previously presented claims 1, 138, 140-141, and 143-150 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Amended and previously presented claims 138, 140-141, and 144-150 are included in this rejection due to their dependence on and/or encompassing of claim 1.
Amended claim 1 now recites, “comprising a 100-200 bp antisense region with a centrally located 50-100 bp region containing the antisense complement of base pairs 1204-1206 of SEQ ID NO: 1418 of an alpha L-iduronidase (IDUA) target RNA sequence”, which has multiple issues of indefiniteness.
Firstly, “centrally located” is indefinite because the engineered guide RNA claimed is circular, and therefore does not have a center along the RNA strand.
Secondly, “the antisense complement of base pairs” is indefinite because “base pairs” requires a double stranded structure whereas the antisense complement can only be directed towards a single stranded sequence.
Thirdly, “of an alpha L-iduronidase (IDUA) target RNA sequence” is further indefinite because it is unclear what the IDUA is “of”. For example, it is unclear whether “of” in line 3 is meant to indicate that the SEQ ID NO: 1418 is an IDUA target RNA sequence or a part of an IDUA target RNA sequence, meant to indicate that the centrally located 50-100 bp region is a region of the IDUA target RNA sequence, or meant to indicate that the 100-200 bp antisense region is a region of the IDUA target RNA sequence.
As such, the metes and bounds of the claim cannot be determined.
Amended claim 143 newly recites, “wherein the circular engineered guide RNA comprising an antisense region of about 100 bp or more”, which conflicts with the limitation of independent claim 1, upon which claim 143 depends, which recites, “A circular engineered guide RNA comprising a … 100-200 bp antisense region” in that “about 100 bp or more” encompasses antisense regions which are more than 200 bp, which is the upper limit required by claim 1. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(a)
The rejection of amended, previously presented, and cancelled claims 1 and 138-150 under 35 U.S.C. 112(a) for failing to comply with the written description requirement is withdrawn over cancelled claims 139 and 142 and maintained over amended and previously presented claims 1, 138, 140-141, and 143-150. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Note that, as discussed above in the rejection under 112(b), claim 1 newly recites, “of an alpha-L-iduronidase (IDUA) target RNA sequence”, which is indefinite for being unclear what is being modified by the recited prepositional phrase. As such, the broadest reasonable interpretation encompasses wherein the “of” indicates that the sequence of SEQ ID NO: 1418 is comprised in an alpha-L-iduronidase (IDUA) target RNA sequence. Therefore, amended independent claim 1 as written does not require that the antisense region be antisense to an IDUA target RNA sequence nor that it comprise a 50-100 bp region which is antisense to an IDUA target RNA sequence. As written, independent claim 1 merely requires that the antisense region comprise a “CCA”, which is the antisense complement of nucleotides 1204-1206 of SEQ ID NO: 1418. Accordingly, the amendments to independent claim 1 have broadened the scope of the claim to encompass circular engineered guide RNAs comprising a 100-200 nucleotide antisense region which is complementary to any target RNA sequence which comprises a TGG sequence.
Although amended claim 1 now recites structural limitations similar to that previously recited in cancelled claim 139 for the antisense region to be 100-200 nucleotides and for a “centrally located” portion of the antisense region to comprise “CCA”, the claims have been broadened dramatically by the amendment such that claim 1 now encompasses any target sequence comprising a “CCA”. Therefore, the genus of circular engineered guide RNA comprising a 100-200 nucleotide antisense region with a centrally located 50-100 nucleotide region containing CCA is a broader genus than the previously claimed genus of engineered guide RNA variants with incomplete complementarity with either 1) an IDUA target RNA sequence including SEQ ID NO: 1418 or 2) the sequence complementary to an IDUA target RNA sequence including the sequence of SEQ ID NO: 1418, wherein the gRNA is capable of targeting the IDUA target RNA to facilitate a gene editing of the IDUA target RNA.
Applicant has not narrowed the claims to a genus which is adequately described in the disclosure. Note that the claim as written still encompasses any level of “antisense” complementarity beyond the requirement to complement the TGG of nucleotides 1204-1206 according to SEQ ID NO: 1418 (i.e., comprise CCA). As such, the claim as written still encompasses variation which may change the structure sufficiently to prevent annealing of the guide RNA to the target RNA sequence and/or direct the guide RNA to preferentially anneal to an alternative non-target sequence.
Accordingly, the amendment to independent claim 1 does not overcome the rejection for a lack of written description under 35 U.S.C. 112(a).
Applicant argues that claim 1 now recites both structure and function and as such is not directed to a broad genus of sequences that have no corresponding structure. However, this is not agreed.
As described above, the limited structural limitations added into claim 1 are accompanied by an expansion of the scope for which RNA target sequences are being targeted by the circular engineered guide RNA. Although the specification generally teaches “target RNAs” [0015] and lists a few alternative targets, namely FANCC, CTNNB1, SMAD4, TARDBP, GAPDH, RAB7A, ALDOA, DAXX, or IDUA [0010, 0020, 0190], the specification does not disclose sufficient structure-function relationships to encompass the broad scope of any circular engineered guide RNA targeted to any target sequence comprising a “CCA” sequence within the “centrally located” 50-100 nucleotides which would achieve the desired on-target editing functionality. The instant disclosure only teaches two different guide RNAs used to target IDUA sequences to correct a mouse W392X mutation along with individual circular engineered guide RNAs targeting each of GAPDH, ALDOA, DAXX, FANCC, CTNNB1, SMAD4, and TARDBP [0168, 0184, 0186, 0189, 0190-0193, Figure 3].
Additionally, the structural components merely limit the size of the antisense region without requiring any level of complementarity nor any specific sequence other than “CCA”, which is an excessively common sequence which does not narrow the scope sufficiently to be consistent with the instant disclosure which only teaches 1 or 2 specific sequences for each of 8 targets.
Therefore, the specification does not describe the claimed circular engineered guide RNAs, in such full, clear, concise, and exact terms so as to indicate that Applicant has possession of these gRNAs able to anneal to any target sequence to recruit the base editor to the target sequence to be edited at the time of filing the present application. Thus, the written description requirement has not been satisfied.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 1 and 138-150 under 35 U.S.C. 103 as being unpatentable over Byrne [US20230203483A1, published 29 June, 2023, with priority to U.S. Provisional Application Nos. 63/013,774, filed 22 April 2020, 63/030,118, filed 26 May 2020, 63/086,434, filed 1 October 2020, 63/112,486, filed 11 November 2020, 63/119,878, filed 1 December 2020, and 63/153,817, filed 25 February 2021]; in view of Bryson et al. [US20230159956A1, published 25 Mary 2023, with priority to U.S. Provisional Application Nos. 62/670,588, filed 11 May 2018, 62/780,838, filed 17 December 2018, and 62/817,986, filed 13 March 2019]; is withdrawn over cancelled claims 139 and 142 and maintained over amended and previously presented claims 1, 138, 140-141, and 143-150. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims to broaden the scope of independent claim 1 to targeting any target RNA sequence comprising “CCA”. Additionally, amended claim 1 to require that the circular engineered guide RNA comprise a 100-200 nucleotide antisense region, which is narrowed compared to the 50-200 nucleotide length previously recited in cancelled claim 139. However, Byrne was cited for teaching to use a 100 nt circular guide RNAs to produce ADAR editing [0021, 0024-0026, 0029, 0399-0402]. Additionally, the sequence taught by Bryson comprises “CCA” in that Bryson was cited for teaching the targeted sequence of the human IDUA polynucleotide sequence (SEQ ID NO: 295) corresponding to nucleic acid 1231-1324 of the human IDUA gene sequence according to Bryson SEQ ID NO: 305, which as seen in the alignment in the prior action corresponds to nucleotides 1190-1283 of instant SEQ ID NO: 1418 and therefore contains nucleotides 1204-1206 of instant SEQ ID NO: 1418 [0855-0856].
Note further that the amendment to claim 144 has also broadened the claim to encompass any linear engineered guide RNA as a reference control without requiring any relationship to the circular engineered guide RNA. For example, the linear control guide RNA does not need to be antisense to the same target RNA nor have any shared sequence with the circular guide RNA. Accordingly, the scope of claim 144 has not been narrowed to overcome the rejection of record.
Accordingly, Applicant’s amendments to the claims do not overcome a finding of obviousness under 35 U.S.C. 103 over Byrne and Bryson.
Applicant argues that neither Byrne nor Bryson alone or in combination teach the sequence and structure recited in claim 1 in that there is nothing in the references alone or combined that teach or suggest a 100-200 bp antisense sequence with a centrally located 50-100 bp region that corresponds to bp 1204-1206 of SEQ ID NO: 1418. However, this is not agreed.
As discussed above, Byrne was cited for teaching a 100 bp circular engineered guide RNA. Additionally, Bryson was cited for teaching targeting an IDUA sequence corresponding to nucleotides 1190-1283 of instant SEQ ID NO: 1418 and therefore comprising 94 nucleotides containing nucleotides 1204-1206 of instant SEQ ID NO: 1418.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Byrne and Bryson, and the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
